Our objective is to study a novel immunotherapy treatment in a Phase I clinical trial in which lesions of chemotherapy refractory melanoma patients are injected with 1-gal glycolipids. This treatment exploits the therapeutic potential of the natural anti-Gal antibody. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts with 1-gal epitopes (Gal11-3Gal21-4GlcNAc-R). 1-Gal glycolipids extracted from rabbit RBC membranes have carbohydrate chains capped with 1-gal epitopes. When injected into tumors, the lipid tails of 1-gal glycolipids insert spontaneously into tumor cell membranes within the lesion. Our preliminary data in a mouse model have indicated that such injection destroys the treated lesions and converts them into endogenous autologous tumor vaccines. Intratumoral injected 1-gal glycolipids bind anti-Gal and induce local inflammation. Tumor cells with the inserted 1-gal glycolipids are destroyed by anti-Gal in a manner similar to anti-Gal mediated xenograft rejection. Anti-Gal further targets the tumor cells with inserted 1-gal glycolipids for effective uptake by APC that are recruited into the treated lesion as part of the inflammatory response. This uptake is mediated by Fc3 receptors on APC that bind effectively the Fc portion of anti-Gal IgG opsonizing the tumor cells. The APC transport internalized autologous melanoma associated antigens (MAA) to draining lymph nodes, process and present the MAA peptides for the activation of melanoma specific T cells, ultimately eliciting a protective immune response against melanoma micrometastases. We aim to complete a Phase I clinical trial of this treatment in stage IV patients with readily injectible melanoma lesions, refractory to standard therapy (FDA-IND 12946). Our specific objectives are: 1. the primary objective is to evaluate toxicity and determine the maximum tolerated dose (MTD) of 1-gal glycolipids injected intratumorally in a dose escalation study. 2. To determine tumor response in treated patients. 3. To evaluate development of immune response to common MAA. If successful, these studies will enable future evaluation of 1-gal glycolipids therapy efficacy in Phase II studies in patients with metastatic melanoma, as well as in patients with other types of solid tumors that are refractory to standard therapy. PUBLIC HEALTH RELEVANCE: We aim to study in a Phase I clinical trial in melanoma patients, a novel treatment that we have developed for cancer patients who do not responds to standard treatment. The proposed treatment includes the direct injection of a substance called 1-gal glycolipids into the tumor lesion. Within the injected tumor, 1-gal glycolipids insert into the tumor cell membranes and interact with the most abundant antibody naturally present in humans, called "anti-Gal". This interaction between anti-Gal and injected 1-gal glycolipids is likely to achieve two objectives: 1. it induces intratumoral inflammation which destroys the treated lesion, and 2. it converts the treated lesion into a vaccine that immunizes the patient against his/her tumor. This immunization results in the development of an immune response that destroys invisible metastatic tumor cells. In the proposed Phase I study we plan to determine the maximum dose which can be safely administered to cancer patients, measure the effect of the treatment on the treated lesion and evaluate the immune response against melanoma, induced in treated patients following intratumoral injection of 1-gal glycolipids. This Phase I study will enable us in the future to apply this treatment to cancer patients that have metastases and who do not respond to standard treatment.